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      Involvement of PI3K/Akt Pathway in TGF-β 2-Mediated Epithelial Mesenchymal Transition in Human Lens Epithelial Cells

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          Background: Epithelial mesenchymal transition (EMT) of postoperative remnants of lens epithelial cells (LECs) can lead to posterior capsule opacification. This study was designed to determine the effect of signaling pathways that contribute to TGF-β<sub>2</sub>-mediated EMT in human lens epithelial B-3 cells (HLEB-3 cells). Methods: The HLEB-3 cells were cultured and stimulated with TGF-β<sub>2</sub> at different concentrations for an indicated time. The effect of TGF-β<sub>2</sub> on cell cycle distribution was measured by flow cytometry. Western blot and immunofluorescence were used to analyze changes in connexin 43, fibronectin, desmin and integrin β<sub>1</sub> protein expression associated with EMT in HLEB-3 cells. Activation of phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways was also detected by Western blot. Results: The cell cycle progression of HLEB-3 cells was limited, and the cells underwent morphological alteration after treatment with TGF-β<sub>2</sub>. Stimulation of HLEB-3 cells with TGF-β<sub>2</sub> suppressed connexin 43 protein expression, increased fibronectin, desmin and integrin β<sub>1</sub> protein expression. TGF-β<sub>2</sub> activated PI3K/Akt in a time-dependent manner, but not extracellular signal-regulated kinase and p38 MAPK. The activation of PI3K/Akt was necessary for the TGF-β<sub>2</sub>-stimulated downregulation of connexin 43, which in turn was necessary for TGF-β<sub>2</sub>-induced EMT in HLEB-3 cells. Conclusions: TGF-β<sub>2</sub> is a potent growth factor for LEC EMT. TGF-β<sub>2</sub>-induced EMT in LECs is mediated by the downregulation of connexin 43, which is regulated through the PI3K/Akt pathway.

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          Most cited references 20

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          Epithelial-mesenchymal transitions in development and pathologies.

          The epithelial-mesenchymal transition (EMT) is a fundamental process governing morphogenesis in multicellular organisms. This process is also reactivated in a variety of diseases including fibrosis and in the progression of carcinoma. The molecular mechanisms of EMT were primarily studied in epithelial cell lines, leading to the discovery of transduction pathways involved in the loss of epithelial cell polarity and the acquisition of a variety of mesenchymal phenotypic traits. Similar mechanisms have also been uncovered in vivo in different species, showing that EMT is controlled by remarkably well-conserved mechanisms. Current studies further emphasise the critical importance of EMT and provide a better molecular and functional definition of mesenchymal cells and how they emerged >500 million years ago as a key event in evolution.
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            Activation of AKT kinases in cancer: implications for therapeutic targeting.

            The AKT1, AKT2, and AKT3 kinases have emerged as critical mediators of signal transduction pathways downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase. An ever-increasing list of AKT substrates has precisely defined the multiple functions of this kinase family in normal physiology and disease states. Cellular processes regulated by AKT include cell proliferation and survival, cell size and response to nutrient availability, intermediary metabolism, angiogenesis, and tissue invasion. All these processes represent hallmarks of cancer, and a burgeoning literature has defined the importance of AKT alterations in human cancer and experimental models of tumorigenesis, continuing the legacy represented by the original identification of v-Akt as the transforming oncogene of a murine retrovirus. Many oncoproteins and tumor suppressors intersect in the AKT pathway, finely regulating cellular functions at the interface of signal transduction and classical metabolic regulation. This careful balance is altered in human cancer by a variety of activating and inactivating mechanisms that target both AKT and interrelated proteins. Reprogramming of this altered circuitry by pharmacologic modulation of the AKT pathway represents a powerful strategy for rational cancer therapy. In this review, we summarize a large body of data, from many types of cancer, indicating that AKT activation is one of the most common molecular alterations in human malignancy. We also review mechanisms of activation of AKT kinases, examples of therapeutic modulation of the AKT pathway in animal models, and the current status of efforts to target molecular components of the AKT pathway for cancer therapy and, possibly, cancer prevention.
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              Structural and functional diversity of connexin genes in the mouse and human genome.

              Gap junctions are clustered channels between contacting cells through which direct intercellular communication via diffusion of ions and metabolites can occur. Two hemichannels, each built up of six connexin protein subunits in the plasma membrane of adjacent cells, can dock to each other to form conduits between cells. We have recently screened mouse and human genomic data bases and have found 19 connexin (Cx) genes in the mouse genome and 20 connexin genes in the human genome. One mouse connexin gene and two human connexin genes do not appear to have orthologs in the other genome. With three exceptions, the characterized connexin genes comprise two exons whereby the complete reading frame is located on the second exon. Targeted ablation of eleven mouse connexin genes revealed basic insights into the functional diversity of the connexin gene family. In addition, the phenotypes of human genetic disorders caused by mutated connexin genes further complement our understanding of connexin functions in the human organism. In this review we compare currently identified connexin genes in both the mouse and human genome and discuss the functions of gap junctions deduced from targeted mouse mutants and human genetic disorders.

                Author and article information

                Ophthalmic Res
                Ophthalmic Research
                S. Karger AG
                February 2008
                25 January 2008
                : 40
                : 2
                : 69-76
                Eye Center, Affiliated Second Hospital, College of Medicine, Zhejiang University, Hangzhou, China
                113884 Ophthalmic Res 2008;40:69–76
                © 2008 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 29, Pages: 8
                Original Paper


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